Process of preparation of alkyl cyclopentane diones and intermediates therefor



United States Patent 01 Efice 3,518,296 Patented June 30, 1970 US. Cl. 260-468 10 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to a new process of preparation of alkyl cyclopentane diones. It more particularly relates to a new process of preparation of 2-alkyl cyclopentane-1,3-diones of the following general Formula I:

in which R represents a lower alkyl radical by reacting a fl-keto ester of the formula R $112 COOR 02 ca 1300B.

wherein R and R are lower alkyl, with analkaline cyclizing agent, saponifying the resultant 2-lower-alkyl-4- carboxylate-cyclopentane-1,3-dione, decarboxylating the resultant 2-lower alkyl-4-carboxy-cyclopentane-1,3dione and recovering said 2-alkyl cyclopentane-1,3-diones. The invention also resides in the intermediate 4-substituted compounds.

The said compounds find their utilization as such as starting materials in the elaboration of steroids carrying an alkyl radical in the 13-position as, for 2 example, estradiol, 13-ethyl-1-8-nor-estradiol, 13-n-propyl-l8-n0restradiol or 13-n-propyl-18,l9bis-nor-testosterone and their derivatives substituted in the l7-position.

Until quite recently, no industrial process for obtaining 2-alkylcyclopentane-1,3-diones was known. These products are of considerable interest. in diverse total syntheses of steroid compounds.

In 1955, the inventors of French Pat. 1,171,930 proposed the first synthesis of Z-methyl-cyclopentane-1,3- dione allowing the obtention of the product with good yields. In this synthesis, the ketone function in the 4-position of 2-methyl-cyclopentane-1,3,4-trione was selectively reduced by the Wolff-Kishner method. The obtention of the starting trione was in two steps starting from ethyl oxalate and methylethylketone.

The present invention has for its object a new method of access to 2-alkyl-cyclopentane-1,3-diones.

Another object of the present invention is the development of a process for the production of a cyclopentanedione of the formula R Fo wherein R represents lower alkyl, which comprises the steps of reacting a ,B-keto ester of the formula wherein R has the above-noted meaning and R represents a lower alkyl with an alkaline cyclizing agent in the presence of an aprotic solvent, saponifying the compound of the formula R -FO 1 COOR wherein R aind R have the above-noted meanings by alkaline hydrolysis, decarboxylating' the compound of the formula R -=o A J wherein R has the above-noted meaning and recovering said cyclopentanedione.

A further object of the invention is the preparation of novel intermediates; a cyclopentane of the formula wherein R represents lower alkyl and R represents a member selected from the group consisting of hydrogen and lower alkyl, and its enolic forms.

These and other objects of the invention will become more apparent as the description thereof proceeds.

We have now found out that it is possible to transform a fi-keto ester into the corresponding dicarbanion by the action of an alkaline agent, a fact which is unexpected as until the present only dicarbanions of B-diketones or ,B-keto aldehydes were known.

We have found, in addition, that the said dicarbanion leads by intramolecular acylation to a cyclization according to the following flow diagram of Table I in which R and R represent lower alkyl radicals.

TABLE I R R R CH2 002R CH 602R O H2 else/CH2 0 COOR COOR 000K and furnishes thus a carboxylated cyclopentane dione which presents the structure of the desired product.

This cyclization constitutes thus the first discovery of an intramolecular acylation of a dianionic form, the dicarbanions having been until the present utilized only in order to elfect alkylations.

The subsequent transformation of the cyclized product into the Z-alkyl-cyclopentane-l,3-dione can easily be completed by conventional saponification and decarboxylation steps.

Thus, the new process occurs with simple reactions and is easy to operate. It permits the avoidance, in particular, of recourse to the reduction according to Wolff-Kishner which, as is known, is relatively laborious in this particular case where it is necessary to use the semi-carbazide as reactant and requires, on the other hand, working at quite elevated temperatures.

The process of the invention is shown by the course of the reactions shown in Table H where R and R have the above-mentioned meanings.

TABLE II (I I) R 6112 COzR' (III) R 0 02B. l (IV) R "o OOH R and R represent the same or different lower alkyls.

The new process of the invention is characterized essentially in that a B-keto ester (II) of the general formula R-CH2 COOR CH 430 OR in which R and R being the same or ditferent represent lower alkyl is subjected to the action of an alkaline agent in the presence of an aprotic solvent. The corresponding 4 carbo lower-alkoxy-2-lower-alkyl-cyclopentane-1,3- dione (III) is obtained and is transformed by saponification of the ester function by alkaline hydrolysis, followed by decarboxylation into the desired 2-lower-alkyl-cycl0- pentane-l,3-dione (I).

As alkaline agents employed for cyclization, one can use advantageously alkaline alcoholates, preferably alkali metal lower alkanolates, such as sodium or potassium t-butylate.

The reaction is conducted in an aprotic solvent. An aprotic solvent is one which is neither a proton acceptor nor a proton donor. Among such aprotic solvents are the hydrocarbons, preferentially a benzenic hydrocarbon, such as, for example, benzene, toluene or xylene, or aliphatic ethers.

The saponification step can be effected in the same cyclization media by the addition to the reaction media of an aqueous alkali metal or alkaline earth base such as the hydroxide, or even by simple addition of water and heating.

Similarly, the decarboxylation step can be elfected without isolating the saponification product by rendering the reaction media acidic by the addition to the reaction media of an acid, such as mineral acids, for example, hydrochloric acid or sulfuric acid and heating.

The decarboxylation can also be eifected by simple sublimation of the saponified product.

It is thus possible according to the present invention to transform a dialkyl alkanoyl-succinate into a 2-loweralkyl-cyclopentane-l,3-dione without changing the reaction media or removing the intermediate products therefrom, thus avoiding any loss of yield in intermediate recovery steps.

As starting compounds, the following fi-keto esters can particularly be utilized:

(a) Di-lower alkyl propionyl-succinate, such as the ethyl ester (II, with R=CH and R==C H in order to obtain 2-methyl-cyclopentane-l,S-dione;

(b) Di-lower alkyl butyryl-succinate, such as the ethyl ester (II, with R=R =C H in order to obtain 2- ethyl-cyclopentane-1,3-dione;

(c) Di-lower alkyl n-valeryl-succinate, such as the ethyl ester (II, with R=CH CH CH R' =C H in order to obtain 2-n-propyl-cyclopentane-1,3-dione;

(d) Di-lower alkyl iso-valeryl-succinate, such as the ethyl ester (II, with R'-=C H in order to obtain Z-isopropyl-cyclopentane- 1,3-dione.

The starting compounds, the di-lower alkyl lower alkanoyl-succinates of Formula II can be readily obtained according to the process described by Friedmann, J. Prakt. Chemie 146, 159 (1936) for the production of diethyl propionyl-succinate (II, R=CH R==C H The author describes the production of diethyl propionylsuccinate in one step by condensation of the sodium derivative of ethyl propionyl-acetate with ethyl bromoacetate. Another process for the preparation of the starting compounds comprises condensing a lower alkanal, such as n-valeraldehyde or isovaleraldehyde, with a di-lower alkyl maleate, such as diethyl maleate in the presence of a small amount of a percompound, such as benzoyl peroxide at elevated temperatures.

The following examples are illustrative of the invention. Other ex-pedients known to those skilled in the art may be employed, however, and the examples are not to be construed as limitative.

EXAMPLE I Preparation of Z-methyl-cyclopentane-1,3-dione (I, with R=CH starting from diethyl propionyl-succinate (II, with R=CH and R=C H Step A: Cyclization.-150 cc. of xylene were added to 50 cc. of a solution of 0.96 N potassium t-butylate in t-butanol. The solution was heated to reflux and over a period of half hour about 60 cc. of ter-butanol were distilled therefrom.

2.3 gm. of diethyl propionyl-succinate (II, with R=CH and R=C H were introduced drop by drop. The distillation was continued for a period of 4 hours at a temperature of about C. There was thus distilled about 40 cc. of xylenic solution which was replaced from time to time by an equal quantity of xylene.

The reaction mixture was next cooled to 0 C. and acidified to a pH of 3 by the slow addition under agitation of 6 cc. of concentrated hydrochloric acid and then the reaction mixture was diluted by 14 cc. of distilled water. Thereafter the reaction mixture was decanted. The aqueous phase was extracted with ether. The extracts were combined with the xylenic fraction and washed with water, dried and concentrated to dryness under vacuum.

1.53 gm. of a product were obtained which product was subjected to chromatography through silica gel with elution with methylene chloride containing 10% of acetone; 710 mg. of 4-carbethoxy-Z-methyl-cyclopentane- 1,3-dione, (III, R=CH R'=C H were obtained having a melting point of 105 C.

The product occurred in the form of white needles, very slightly soluble in water and dilute aqueous acids, soluble in alcohols, ether, acetone, benzene and chloroform.

Analysis. C H O (molecular weight=184.19). Calculated (percent): C, 58.68 H, 6.56. Found (percent): C, 58.958.7; H, 6.66.8%.

This compound is not described in the literature.

The further elution of the chromatographic column with methylene chloride containing 25% and 50% of acetone funished 370 mg. of 4-carboxy-2-methyl-cyclopentane-1,3-dione. (IV, with R=CH having a melting point of 160 C.

The product occurred in the form of white needles, slightly soluble in ether, soluble in water, dilute aqueous acids and alkalis, alcohols, acetone, benzene and chloroform.

This compound is not described in the literature.

Step B: Saponification.600 mg. of 4-carbethoxy-2- methyl-cyclopentane-1,3-dione, (III, with R=CH and R=C H were introduced into 20 cc. of distilled water. 1.92 gm. of barium hydroxide were added and the reaction mixture was heated to reflux for a period of 4 hours under an atmosphere of nitrogen.

Thereafter the reaction mixture was cooled to C. and acidified to a pH of 3 by the addition of 12 cc. of N-hydrochloric acid solution. The mixture was concentrated to dryness under vacuum and 1.815 gm. of residue were obtained. The residue was extracted with hot acetone. The acetonic solution was concentrated to a small volume and filtered. The product obtained was recrystallized from isopropyl ether. About 320 mg. of 4 carboxy 2 methyl-cyclopentane-l,3-dione (IV, with R=CH were obtained having a melting point of 160 C.

Step C: Decarboxylation.200 mg. of 4-carboxy- Z-methyl-cyclopentane-1,3-dione, (IV, with R=CH were introduced into 5 cc. of N-hydrochloric acid solution. The reaction mixture was heated to reflux for a period of one hour, cooled and concentrated to dryness under vacuum.

210 mg. of a product were obtained which product was triturated in hot isopropyl ether. The solution was iced and vacuum filtered. The precipitate was washed with isopropyl ether and dried. 145 mg. of 2-methylcyclopentane-1,3-dione, (I, with R=CH were obtained having a melting point of 214 C.

The product occurred in the form of white prisms, insoluble in ether, acetone and benzene, slightly soluble in water, dilute aqueous acids and chloroform and soluble in alcohols and dilute aqueous alkalis.

Analysis.--C H O (molecular weight=1l2.12). Calculated (percent): C, 64.27; H, 7.18. Found (percent): C, 64.0; H, 7.2.

The product is identical to the product described in the literature.

The starting product, diethyl propionyl-succinate can be easily prepared according to Friedmann, J. Prakt. Chemie 146, p. 159 (1936) in a single step by condensation of the sodium derivative of ethyl propionyl-acetate with ethyl bromo-acetate.

EXAMPLE II Preparation of 2-methyl-cyclopentane-1,3-dione (I, with R=C1H without isolation of the intermediate products (starting from diethyl propionyl-succinate) 250 cc. of 0.96 N potassium t-butylate in t-butanol were introduced into 800 cc. of xylene. The solution was heated to reflux and over a half hour about 300 cc. were distilled therefrom. Thereafter 11.5 gm. of diethyl propionyl-succinate (II, with R=CH and R'=C H were introduced drop by drop into the xylenic solution under an atmosphere of nitrogen and the distillation was con- 6 tinned for a period of 4 hours at a temperature of about 140 C.

.During this time there was thus distilled 200 cc. of xylenic solution which was replaced from time to time by a same amount of xylene.

Next the reaction mixture was cooled in order to bring the temperature of the reaction mixture to C. At this temperature, 200 cc. of water were slowly added and the reflux was continued for a period of 2 hours. After cooling the reaction mixture to room temperature, the aqueous phase was decanted and acidified to a pH of 2 with diluted hydrochloric acid. Thereafter the aqueous phase was concentrated to dryness under vacuum. The product was sublimed from the residue obtained by heating it to a temperature of 200 C. for a period of 20 minutes under vacuum (1 mm. of mercury). 5.20 gm. of 2-methyl-cyclopentane-1,3,-dione (I, with R=CH were obtained.

The product obtained was triturated in 10 cc. of hot isopropyl ether. The solution was iced. The precipitate was vacuum filtered, washed with isopropyl ether and dried. 4.07 gm. of Z-methyl-cyclopentane-l,3-dione (I, with R=CH were obtained having a melting point of 214 C.

The product occurred in the form of white prisms, insoluble in ether, acetone and benzene, slightly soluble in water, dilute aqueous acids and chloroform and soluble in alcohols and dilute aqueous alkalis.

Analysis.C H O (molecular weight=112.12). Calculated (percent): C, 64.27; H, 7.18. Found (percent): C, 64.0; H, 7.2.

EXAMPLE III Preparation of 2-ethyl-cyclopentane-1,3-dione (I, with R=C H starting from diethyl butyryl-succinate Step A: Cyclization.-320 cc. of xylene were added to 100 cc. of a normal solution of potassium t-butylate in t-butanol. The solution was heated to reflux and over a period of a half hour about cc. was distilled therefrom. Thereafter 4.85 gm. of diethyl butyryl-succinate (II, with R=R=C H obtained according to Franke et al. Monatshefte 69, 192 (1936), were introduced drop by drop and the distillation was continuted for a period of 4 hours at a temperature of about C. During this time there was thus distilled 90 cc. of xylenic solution which was replaced from time to time by an equal amount of xylene.

Step B: Saponification.-To the reaction mixture obtained in the preceding step were added 80 cc. of distilled water and the mixture was heated to reflux for a period of 2 hours under an atmosphere of nitrogen.

Thereafter the reaction mixture was cooled and allowed to separate. The organic phase was separated and eliminated. The aqueous phase was acidified to a pH of 2 by the addition of hydrochloric acid solution.

By distillation of the acidified aqueous phase to dryness, 4 carboxyl-l-oxo-3-hydroxy-2-ethyl-cyclopentene-Z (enolic form of 4-carboxy-2-ethyl-cyclopentane-1,3-dione) (IV, with R=CH was obtained in mixture with potassium chloride.

. This compound is not described in the literature.

Step C: Decarboxylation.The product obtained above was sublimed by heating it to about 200-250 C. under vacuum (2 mm. of mercury). 2.18 gm. of Z-ethyl-cyclopentane-1,3-dione (I, with R=C H were obtained.

The product obtained was triturated in hot isopropyl ether. The solution was iced. The precipitate was vacuum filtered, washed and dried. 1.976 gm. of a product were obtained which after recrystallization into a mixture of water and ethanol (12:1) melted at C.

The 2-ethyl-cyclopentane-1,3-dione occurred in the form of white crystals and was soluble in dilute aqueous alkalis and alcohol, slightly soluble in water and dilute aqueous acids and insoluble in ether and benzene.

Analysis.-C-;H O (molecular weight=126.15). Cal- 7 culated (percent): C, 66.64; H, 7.99. Found (percent): C, 68.8; H, 8.1.

EXAMPLE IV Preparation of 2-n-propyl-cyclopentane-1,3-dione (I, with R=-CH CH CH Step A: 1-oxo-2-n-propyl-3-hyd1'oxy-4-carboxy-cyclopentene-Z (IV, enolic form of 2-n-propyl-4-carboxy-cyclopentane-1,3-dione with R=CH -CH --CH Cyclizati0n.103 cc. of 0.96 N solution of potassium t-butylate in t-butanol were introduced into 320 cc. of anhydrous xylene. The mixture formed was heated to reflux for a period of a half hour in order to distill therefrom 150 cc. Over the space of a quarter of an hour, while maintaining energetic agitation, 5.2 gm. of diethyl valeryl-succinate (II, with R=CH C H CH and R C H were added.

The reaction mixture was heated to 137 C. for a period of 4 hours and 150 cc. were distilled therefrom which was replaced with xylene from time to time during its elimination. A suspension of 1-oxo-2-n-propyl-3- hydroxy-4-carboethoxy-cyclopentene-2 (III, enolic form of 2-n-propyl-4-carboethoxy-cyclopentane-1,3-dione, with R: CH CH CI-I and R=C H in xylene was obtained which was not separated and which was utilized as such for the following operation.

This compound is not described in the literature.

In an analogous manner by cyclization of diethyl isovaleryl-succinate, 1-oxo-2-isopropyl 3 hydroxy-4-carboethoxy-cyclopentene-Z (III, enolic form of 2-isopropyl-4- carbethoxy-cyclopentane-1,3-dione, with and R:C H was obtained.

This compound is not described in the literature.

Step B: Saponification.The suspension of l-oxo-Z-npropyl-3-hydroxy-4-carboethoxy-cyclopentene-Z thus obtained was allowed to cool to a temperature of 100 C. and 80 cc. of water were slowly added thereto. Thereafter the mixture was heated to reflux for a period of 2 hours under lively agitation.

Next the reaction mixture was cooled. The aqueous phase was decanted. The organic phase was washed with water and the wash waters were combined with the aqueous phase. The combined aqueous phase was acidified with hydrochloric acid and evaporated to dryness under vacuum. 1-oxo-2-n-propyl 3 hydroxy- 4 -carboxy-cyclopentene-2 (IV, enolic form of 2-n-propyl-4-carboxy-cyclopentane-1,3-dione, with R=CH -CH CH was obtained. This product was utilized as such for the following operation.

This compound is not described in the literature.

In an analogous manner by saponification of l-oxo-Z- isopropyl-3-hydroxy-4-carboethoxy cyclopentene-2 there was obtained 1-oxo-2-isopropyl-3-hydroxy-4-carboxycyclopentene-2 (IV, enolic form of 2-isopropyl-4-carboxy cyclopentane-l,3-dione, with This compound is not described in the literature.

Step C: Decarboxylation.The raw product, the enolic form of 2-n-propyl-4-carboxy-cyclopentane-1,3-dione with R=-CH CH CH obtained precedingly, was heated to a temperature of 200 C. under a vacuum of 2 mm. and 2.42 gm. of Z-n-propyl-cyclopentane-1,3-dione (l, with R=CH CH CH were recovered on a cold surface in the form of yellow crystals which were purified by trituration with hot isopropyl ether.

The solution was iced. The precipitate was vacuum filtered and washed with iced isopropyl ether. 1.5 gm. of Z-n-propyl-cyclopentane-1,3-dione (I, with were obtained having a melting point of C.

The product occurred in the form of white crystals, insoluble in water and the most part of the usual organic solvents such as benzene, alcohol, acetone, chloroform and ether.

In an analogous manner by decarboxylation of l-oxo- 2-isopropyl-3-hydroxy 4 carboxy cyclopentene-2 (IV, enolic form of 2-is0propyl-4-carboxy-cyclopentane-1,3-

dione,

there was obtained 2-isopropylcyclopentane-1,3-dione (I, with The product melted at 218 C. with sublimation.

The product occurred in the form of needles insoluble in ether, benzene and chloroform, slightly soluble in water and dilute aqueous acids and soluble in dilute aqueous alkalis and alcohols.

Analysis.-C H O (molecular Weight=140.l8). Calculated (percent): C, 68.54; H, 8.63. Found (percent): C, 68.2; H, 8.7.

The starting products diethyl valeryl-succinate and diethyl isovaleryl-succinate could be prepared as indicated hereafter.

Preparation of diethyl valeryl-succinate (II, with R=CH CH -CH and R'ZCZH5) 33 gm. of valeraldehyde and 21 gm. of diethyl maleate were mixed and heated to 60 C. 0.95 gm. of benzoyl peroxide were added thereto. Then the heating was continued for a period of 18 hours at 75 C. The reaction mixture was cooled, washed with 30 cc. of a saturated aqueous solution of sodium bicarbonate. 25 cc. of methylene chloride were added thereto. The organic phase was decanted, washed with water until the wash waters were neutral and dried.

The methylene chloride was removed therefrom by distillation under vacuum and diethyl valeryl-succinate was recovered (II, with R=CH CH -CH and R'=C H This compound is not described in the literature.

In an analogous manner, starting from iso-valeraldehyde, diethyl isovaleryl-succinate (II, with of the formula wherein R represents lower alkyl which comprises the steps of reacting a ,B-keto ester of the formula R (3H2 COOR' CH 1 JOOR' wherein R represents lower alkyl and R represents a member selected from the group consisting of hydrogen and lower alkyl, and its enolic forms.

3. 2-methy1-4-carboxy-cyclopentane-1,3-dione and its 30 enolic forms.

4. 2-ethyl-4-carboxy-cyclopentane 1,3 dione and its enolic forms.

5. 2-n-propyl-4-carboxy-cyclopentane 1,3 dione and its enolic forms.

6. 2-isopropyl-4-carboxy-cyclopentane 1,3 dione and its enolic forms.

7. 2-methyl-4-carbethoxy-cyclopentane 1,3 dione and its enolic forms.

8. 2-ethyl-4-carbethoxy-cyclopentane 1,3 dione and its enolic forms.

9. 2-n-propyl-4-carbethoXy-cyclopentane 1,3 dione and its enolic forms.

10. 2-isopr0pyl-4-carbethoxy-cyclopentane 1, 3 dione and its enolic forms.

References Cited UNITED STATES PATENTS 10/1957 Sannie et al. 260586 12/1958 Krimen et al. 260468 XR OTHER REFERENCES JAMES A. PATTEN, Primary Examiner P. I. KILLOS, Assistant Examiner US. Cl. X.R.

22%;? UNITED STATES PATENT OFFICE CERTIFICATE OF COR UBCTION 'Patcot No. Dated June 9 ROBERT BUCOURI e1; 8.1

- Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, Line 9 French Priority Applications PV 932,865 dated Apr.26,1963,"

PV 9h1.0o3 dated Jul.l0,l963

and PV 957,944 dated December 20,1963

were not indicated in the patent.

Signed and sealed this 9th day of May 1972 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

